Over the last year, NISC operated the following suite of production sequencing machines: 1 PacBio RS II, 4 HiSeq 2500s, 1 HiSeq 4000, 1 NovaSeq 6000, and 3 MiSeqs. Using these platforms, we have generated over 770 billion reads in the past year. Though we remain consistently at a level of a mid-scale genome sequencing center, we have maintained advantageous economies of scale while remaining relatively agile. The addition of the NovaSeq 6000 allows NISC to effectively meet the rising interest in studying whole genome sequence datasets. The adoption of many new sequencing protocols in production created the commensurate need for dramatic changes to sample tracking, flow control and primary analysis pipelines, as well as project management and cost accounting. Rapid design, development and implementation of new Laboratory Information Management System (LIMS) by a dedicated NISC team has met the initial challenges and continues to evolve quickly to adapt to a continuous flow of changes in sequencing technologies. A combination of talented IT staff and bioinformaticians have met the challenges of extremely large and complex data sets by implementing and continuously adapting pipeline programs to support rapidly evolving software associated with each of the sequencing platforms. Beyond primary analysis that results in DNA basecalls and quality scores, NISC has worked closely with members of other NHGRI research groups to implement and support high-throughput production of biologically relevant secondary analysis. One shining example of these efforts is the production scale processing of Whole Exome Sequencing (WES) data for all of our clients, the end product of which is distilled sets of variants of interest that are accessible in user-friendly fashion by the use of the in-house developed VarSifter program. The success of these programs has led to an increasing number of projects from a growing number of investigators. In 2014 we added a CLIA compliant pipeline for WES of samples originating from the NIH Clinical Center through the Clinical Center Genomics Opportunity program (https://www.genome.gov/27558725). Since the conclusion of the CCGO project, additional projects requesting the CLIA exome test has led to the processing of another 722 samples for three different groups at NIH. Publications for fiscal-year 2018 span a wide range of projects, and are summarized as follows: 1) Custom capture (n=3) (Asur, Kimble et al. 2018, Kimble, Lach et al. 2018, Roessler, Hu et al. 2018) 2) WES projects (n = 4) (Fleming, Doherty et al. 2017, Gourh, Remmers et al. 2018, Le Gallo, Rudd et al. 2018, Strongin, Heller et al. 2018) 3) Whole Genome Sequencing, Assembly and/or Annotation (n = 1) (Randall, Mullikin et al. 2018) 4) RNAseq, ChIPseq, and ATACseq (n = 3) (Crawford, Kelly et al. 2017, Harris, Fufa et al. 2018, Heuston, Keller et al. 2018) 5) Methylome (n = 1) (Duncan, Grimm et al. 2018) 6) Microbiome study (n = 1) (Weingarten, Johnson et al. 2018) 7) HIV and antibody study (n=1) (Zhou, Zheng et al. 2018) In the foreseeable future, NISC is well positioned to provide next-gen sequence data for a multitude of investigators across NIH. We also expect increasing access to sequencing by the NIH Clinical Center with our CLIA exome test, and continuing our sequencing support for Intramural NHGRI investigators for their most promising projects. Our focus is to increase operational efficiencies of the next-gen pipeline, refine existing protocols, implement additional protocols as new sample/experimental types are requested from researchers and continue to expand the value-added data analysis packages available. Furthermore, we will continue to monitor developments in the rapidly evolving sequencing and informatics technologies, implementing those we deem most appropriate for our collaborating investigators. For example, in the previous year we have had great success with single-cell RNA-seq and have generated extremely long reads, approaching 1,000,000 bases and N50 read-lengths over 70,000 bases, using the Oxford Nanopore GridION system.